Novel berberine-based derivatives with potent hypoglycemic activity

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.     

Novel nucleotide phosphonate analogues with potent antitumor activity

We have identified several nucleotide phosphonates demonstrating in vitro antiproliferative activity in several human cancer cell lines with IC(50) values in the microM range. The synthesis as well as structure-activity relationship are described.     

Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity

A series of polyaminoguanidines and polyaminobiguanides were synthesized and evaluated as potential antitrypanosomal agents. These analogues inhibit trypanothione reductase (TR) with IC50 values as low as 0.95 microM, but do not inhibit the closely related human enzyme glutathione reductase (GR). The most effective analogues, 7a, 7b and 8d, inhibited parasitic growth in vitro with IC50 values of 0.18, 0.09 and 0.18 microM, respectively. These agents represent a promising new class of potential antitrypanosomal agents.     

Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity

The design, synthesis, and structure–activity relationship (SAR) of a series of novel nonpeptidic cyclic phosphon- and phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases MMP-1, MMP-3, and MMP-9 are presented. Based on modelling studies and X-ray analysis, a model of the binding mode of these novel compounds in the MMP active site was obtained. This model provided a rational explanation for the observed SAR data, which included a systematic study of different S1′ directed substituents, zinc-complexing groups, chirality, and variation of the cyclic phosphon- and phosphinamide rings. The in vivo effect of four compounds in a human fibrosarcoma mouse model (HT1080) was evaluated and compared to that of a reference compound, Prinomastat. Inhibition of tumour growth was observed for all four compounds.     

Novel piperazines: potent melanocortin-4 receptor antagonists with anxiolytic-like activity

In the present study, we found that a novel piperazine compound, 11a, showed a moderate affinity (IC(50)=333nM) for the MC4 receptor. We developed the new type of piperazine compounds and found that mono-piperazine 11b exhibited a high-affinity (IC(50)=40.3nM) for the MC4 receptor. We also found that a series of biphenyl analogues exhibited a high-affinity for the receptor, and in particular, compound 11j exhibited the highest affinity for the MC4 receptor with an IC(50) value of 14.5nM. Furthermore, some of these compounds, when administered orally, significantly reversed the stress-induced anxiety-like behavior in rats. In this paper, we report the synthesis, structure-activity relationships, and oral activity of the novel mono-piperazines as MC4 receptor antagonists.     

Novel 5-vinyl pyrimidine nucleosides with potent anti-hepatitis B virus activity.

Synthesis and antiviral activities of novel N-1 alkyl substituted pyrimidines, 1-[(2-hydroxyethoxy)methyl]-5-vinyluracil (5), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-vinyluracil (6), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-vinyluracil (7) are reported. Compounds 6 and 7 were potent inhibitors of DHBV in cell culture, in contrast, all of the compounds described were devoid of activity against TK(+) HSV-1 and TK(-) HSV-1.     

Novel stable PACAP analogs with potent activity towards the PAC1 receptor

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38- or 27-amino acid neuropeptide with promising therapeutic applications for the treatment of several pathophysiological states related to neurodegenerative diseases. However, its use for therapeutic applications is actually limited by its restricted bioavailability and rapid degradation. Therefore, metabolically stable PACAP analogs represent promising tools to further investigate the physiological roles of PACAP and ascertain its usefulness in some clinical conditions. In this study, derivatives of PACAP27 and PACAP38 have been rationally designed to develop PAC1 receptor agonists resistant to peptidase action. Results showed that N-terminal modifications confer resistance to dipeptidyl peptidase IV, a major proteolytic process involved in PACAP degradation. Moreover, in vitro incubation of both PACAP isoforms in human plasma revealed that PACAP38 is rapidly metabolized, with a half-life of less than 5 min, while PACAP27 was stable in these experimental conditions. Hence, following the elucidation of its plasmatic metabolites, PACAP38 was modified at its putative endopeptidase and carboxypeptidase sites of cleavage. All peptide analogs were tested for their ability to bind the PAC1 receptor, as well as for their potency to induce calcium mobilization and inhibit PC12 cell proliferation through the PAC1 receptor. This approach revealed two leading compounds, i.e. acetyl-[Ala¹⁵, Ala²⁰]PACAP38-propylamide and acetyl-PACAP27-propylamide, which exhibited improved metabolic stability and potent biological activity. This study describes innovative data related to PACAP metabolism in human plasma and depicts the development of a metabolically stable PACAP38 analog, acetyl-[Ala¹⁵, Ala²⁰]PACAP38-propylamide, which behaves as a super-agonist towards the PAC1 receptor.     

Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis

A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.     

Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma

Cyclin-dependent kinases (CDKs) and Polo-like kinases (PLKs) play key role in the regulation of the cell cycle. The aim of our study was originally the further development of our recently discovered polo-like kinase 1 (PLK1) inhibitors. A series of new 2,4-disubstituted pyrimidine derivatives were synthesized around the original hit, but their PLK1 inhibitory activity was very poor. However the novel compounds showed nanomolar CDK9 inhibitory activity and very good antiproliferative effect on multiple myeloma cell lines (RPMI-8226).     

2-(3-Amino-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide: a new tiazofurin analogue with potent antitumour activity

A new tiazofurin analogue, 2-(3-amino-3-deoxy-beta-d-xylofuranosyl)thiazole-4-carboxamide (3), was synthesized starting from d-glucose and evaluated for its in vitro antiproliferative activity against a panel of human tumour cell lines. Compound 3 exhibited the most powerful cytotoxicity against K562 cells, being approximately 100-fold more potent than tiazofurin. This analogue was also active against Jurkat, HT-29 and HeLa malignant cells, with respective IC(50) values being ca. 2-, 27- and 17-fold lower than those observed for tiazofurin. Remarkably, compound 3 did not exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cell line.     

Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series

Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.     

Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.     

Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity

Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.     

MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.     

Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis

Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.     

Novel Gemini vitamin D(3) analogs have potent antitumor activity

The active form of vitamin D(3), 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], modulates proliferation and induces differentiation of many cancer cells. A new class of analogs of vitamin D(3) has been synthesized, having two side-chains attached to carbon-20 (Gemini) and deuterium substituted on one side-chain. We have examined six of these analogs for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP, PC-3, DU145), lung (H520), colon (HT-29), and breast (MCF-7) cancer cell lines. Dose-response clonogenic studies showed that all six analogs had greater antiproliferative activities against cancer cells than 1,25(OH)(2)D(3). Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 1,25(OH)(2)D(3) in causing 50% clonal growth inhibition (ED(50)) of HL-60 cells. Pulse-exposure studies demonstrated that exposure to BXL-01-120 (10(-9)M, 48h) resulted in 85% clonal inhibition of HL-60 growth. BXL-01-0120 (10(-11)M, 4 days) induced the differentiation marker, CD11b. Also, morphologically differentiation was more prominent compared to 1,25(OH)(2)D(3). Annexin V assay showed that BXL-01-0120 (10(-10)M, 4 days) induced significantly (p<0.05) more apoptosis than 1,25(OH)(2)D(3). In summary, these analogs have a unique structure resulting in extremely potent inhibition of clonal proliferation of various types of cancer cells, especially HL-60 cells.     

Novel potent dual inhibitors of CK2 and Pim kinases with antiproliferative activity against cancer cells

A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization.     

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity against Escherichia coli-induced interleukin-8 production

Sixteen novel depsides were synthesized for the first time. Their chemical structures were clearly determined by ¹H NMR, ESI mass spectra, and elemental analyses. All the compounds were assayed for antibacterial activities against three Gram-positive bacterial strains (Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, and Streptococcus faecalis ATCC 9790) and three Gram-negative bacterial strains (Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 13525, and Enterobacter cloacae ATCC 13047) by the MTT method. Compound 2-(2-methoxy-2-oxoethyl)phenyl 5-bromonicotinate (5) exhibited significant antibacterial activities against E. coli ATCC 35218 with an MIC of 0.78 μg/mL, which was superior to the positive control kanamycin B. In addition, compound 5 showed potent inhibitory activity against E. coli-induced interleukin-8 production.     

Novel and potent anti-malarial agents

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC50 values from 7 to 35 nM against chloroquine-sensitive and 70-350 nM against chloroquine-resistant strains of Plasmodium falciparum.